Compositions for conjugated estrogens and associated methods

ABSTRACT

Oral conjugated estrogen formulations are disclosed and described. In one aspect, the oral formulation may be a tablet having a core and one or more coatings thereon. In addition to conjugated estrogen ingredients, the core may include one or more organic excipients and one or more inorganic excipients. In one aspect, the organic excipients may include less than about 20% w/w of a cellulose ingredient, and less than about 50% w/w of a sugar ingredient. In another aspect, the inorganic excipients may include less than about 10% w/w of a calcium phosphate tribasic ingredient. In yet another aspect, the formulation does not crack when stored at about 40 ° C. and about 75% relative humidity for about 2 months.

PRIORITY DATA

This application claims priority to U.S. Provisional Patent applicationSer. No. 60/268,177, filed on Feb. 12, 2001, which is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates generally to conjugated estrogenformulations and methods of administering such compositions.Accordingly, this invention covers the fields of pharmaceuticalsciences, medicine, cosmetics, and related sciences.

BACKGROUND OF THE INVENTION

Conjugated estrogens have been used for years as an estrogen supplementin order to treat or prevent a variety of conditions that are induced orexacerbated by estrogen hormone deficiency. Particularly, conditionsexperienced by peri-menopausal, menopausal, and post-menopausal womensuch as osteoporosis, hot flashes, vaginal atrophy, and loss ofprotection against heart attacks, can be ameliorated using conjugatedestrogens as part of an estrogen replacement therapy routine.

Although conjugated estrogens may be administered using various routesof administration, oral tablet administration has traditionally been themost common. Such formulations have not only contained conjugatedestrogens, but have also included other hormones, such as progesteronein order to balance the physiological effects of estrogensupplementation. For example, oral estrogen replacement tabletscontaining either a conjugated estrogen, or combination of conjugatedestrogen and medroxyprogesterone acetate are currently marketed underthe trade names PREMARIN®, PREMPRO™, and PREMPHASE®, by Wyeth-AyerstLaboratories, Inc.

While oral tablet regimens of conjugated estrogen have been able toachieve acceptable therapeutic results, various drawbacks to known oraltablet formulations still exist. Example of such a drawbacks includeerratic drug release, degradation of the conjugated estrogen, andcracking of the tablet formulation during storage.

A variety oral tablet formulations of both instant and sustained releasefor administering conjugated estrogen are currently known. For example,U.S. Pat. No. 5,395,627, which is incorporated herein by reference inits entirety, discloses pharmaceutical granulates and process for makinggranulates to be used in oral tablet manufacture, which are veryresistant to segregation, and which display an increased stability forcertain steroids, such as estrogens and progestogens.

U.S. Pat. No. 5,547,948, which is incorporated herein by reference inits entirety, discloses a sugar coating composition for application to acompressed medicinal tablet used to co-deliver two or morepharmacologically-active agents. Particularly, the sugar coatingcomposition includes sugar, a therapeutic amount of a hormonal steroid,and a hormonal steroid release-controlling amount of microcrystallinecellulose. The tablet core contains a medicinal agent which isconventionally co-delivered with the specific steroid in the sugarcoating.

U.S. Pat. No. 5,720,977, which is incorporated herein by reference inits entirety, discloses an effervescent oral formulation containing awater-soluble and stable estrogen compound, such as estropipate, orestrone, a water soluble calcium salt, and a pharmaceutically acceptableexcipient. The effervescent activity of the tablet is purported to aidthe body's absorption of estrone and other estrogens due to their waterinsoluble nature. Further, the calcium component of the effervescentcausing ingredients may be used as a calcium supplement to furtherprotect against bone loss and osteoporosis.

U.S. Pat. No. 5,908,638, which is incorporated herein by reference inits entirety, discloses a solid dosage unit form containing low doseconjugated estrogens that are released at regular increments (i.e.sustained release) upon oral administration. Generally, the sustainedrelease of estrogens and other hormones, when included, is accomplishedby the inclusion of a high molecular weighthydroxypropylmethylcellulose, which may be further combined with otherhydrophilic gums. In addition to controlled release, this patentdiscloses that strict control of moisture content within the formulationis essential to stabilizing conjugated estrogens and achieving a uniformrelease thereof.

In spite of the foregoing, problems such as insolubility, instability,and tablet cracking associated with oral conjugated estrogen tabletsstill persist. Therefore, an oral tablet formulation which overcomes, orat least ameliorates, these shortcomings continues to be sought throughongoing research and development efforts.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides, a pharmaceuticalcomposition in a solid oral dosage form which does not crack afterstorage at about 40° C. and about 75% relative humidity for about 2months. In other words, the compositions are stable under ambientconditions in most environments. In one aspect, the solid oral dosageform may be a tablet having a core containing a therapeuticallyeffective amount of a conjugated estrogen, or a hormonal componentthereof, at least one organic excipient, at least one inorganicexcipient. A variety of specific conjugated estrogens and specificamounts thereof may be included. However, in one aspect, the conjugatedestrogen maybe present in an amount of from about 0.1 mg to about 3 mg.In another aspect, the amount may be about 0.625 mg.

A variety of organic excipients may be used in the core of the presentoral formulation. In one aspect, the organic excipients may include lessthan about 25% w/w of a cellulose ingredient, and less than 50% w/w of asugar ingredient. Further, while a variety of inorganic excipients maybe used, in one aspect, the inorganic excipients may include less thanabout 10% w/w of a calcium phosphate tribasic ingredient.

In addition to the core recited above, the oral formulation of thepresent invention may include an outer coating. In one aspect, thecoating may be substantially free of hormones. In another aspect, thecoating may contain one or more sugar ingredients. In yet anotheraspect, the coating may include one or more acrylic polymers.

There has thus been outlined, rather broadly, the more importantfeatures of the invention so that the detailed description thereof thatfollows may be better understood, and so that the present contributionto the art may be better appreciated. Other features of the presentinvention will become clearer from the following detailed description ofthe invention, taken with the accompanying drawings and claims, or maybe learned by the practice of the invention.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a graphical representation of the comparative drug releaseresults achieved for various sugar coated 0.625 mg dose conjugatedestrogen tablets, as compared to a Premarin® tablet as a control.

FIG. 2 shows a graphical representation of the comparative drug releaseresults achieved for various acrylic coated 0.625 mg dose conjugatedestrogen tablets, as compared to a Premarin® tablet as a control.

DETAILED DESCRIPTION

Before the present invention is disclosed and described, it is to beunderstood that this invention is not limited to the particularstructures, process steps, or materials disclosed herein, but isextended to equivalents thereof as would be recognized by thoseordinarily skilled in the relevant arts. It should also be understoodthat terminology employed herein is used for the purpose of describingparticular embodiments only and is not intended to be limiting.

Definitions

In describing and claiming the present invention, the followingterminology will be used.

The singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a polymer” includes reference to one or more types of polymers, andreference to “an estrogen” includes reference to one or more types ofestrogen.

The term “formulation” and “composition” may be used interchangeablyherein.

The phrases “therapeutically effective amount” refers to an amount ofconjugated estrogen sufficient to achieve therapeutic or adequatehormone supplementation results. The determination of an effectiveamount is well within the ordinary skill in the art of pharmaceutical,cosmetic, and medical sciences. See, for example, Meiner and Tonascia,“Clinical Trials: Design, Conduct, and Analysis,” Monographs inEpidemiology and Biostatistics, Vol. 8 (1986), incorporated by referencein its entirety.

The phrase “substantially free” refers to the absence of a specificagent or compound, or if present, such agent or compound is present inan amount that does not provide its functional purpose to a measurabledegree. For example, a tablet coating that is substantially free of ahormone may be either totally hormone free, or contain such a minuteamount of hormone, so as to provide no measurable physiological effect.

The term “administration” refers to oral delivery of conjugatedestrogen. This method and other methods of administration are well knownto those in the pharmaceutical arts.

The term “cellulose” refers to a polysaccharide consisting ofanhydroglucose units joined by an oxygen linkage to form long molecularchains that are essentially linear. A number of specific celluloseinclusive compounds are known and used as excipients in thepharmaceutical arts, including without limitation,hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxyethylcellulose, hydroxybutylethylcellulose,hydroxybutylmethylcellulose, ethylcellulose, carboxymethylcellulose,sodium carboxymethylcellulose, as well as other cellulose derivatives.As such, the recitation of the term “cellulose” generically, should beinterpreted to include such specific cellulosic compounds, as well asothers not expressly recited.

The term “sugar” refers to any type of simple carbohydrate, such as amono or disaccharide, or a combination thereof, either naturallyobtained, refined from a natural source, or artificially produced. Avariety of sugars are known and used in various pharmaceuticalformulations, including without limitation, sucrose, glucose, mannose,fructose, lactose, etc. As such, the recitation of the term “sugar”generically, should be interpreted to include such specific compounds,as well as others not expressly recited.

Concentrations, amounts, solubilities, and other numerical data may beexpressed or presented herein in a range format. It is to be understoodthat such a range format is used merely for convenience and brevity andthus should be interpreted flexibly to include not only the numericalvalues explicitly recited as the limits of the range, but also toinclude all the individual numerical values or sub-ranges encompassedwithin that range as if each numerical value and sub-range is explicitlyrecited.

As an illustration, a concentration range of “about 1% w/w to about 10%w/w” should be interpreted to include not only the explicitly recitedconcentration of about 1% to about 10% w/w, but also include individualconcentrations and the sub-ranges within the indicated range. Thus,included in this numerical range are individual concentrations such as2% w/w, 5% w/w, and 8% w/w, and sub-ranges such as from 1% w/w to 3%w/w, from 2% w/w to 4% w/w, from 3% w/w to 8% w/w, from 5% w/w to 9%w/w, from 1% w/w to 7% w/w etc. The same principle applies to rangesreciting only one numerical value.

Similarly, an open ended range recited as “less than about 10% w/w”should be interpreted to include all of the values and ranges aselaborated above for the range of “from about 1% w/w to about 10% w/w.”Furthermore, it is understood that functional limitations may exist forlimits not expressly recited by an open ended range, and that suchlimitations are inherently included as part of the disclosure of thepresent application, though not expressly recited. Such aninterpretation should apply regardless of the breadth of the range orthe characteristics being described.

Invention

The present invention relates to a formulation comprising a corecontaining conjugated estrogens, one or more inorganic excipients, oneor more organic excipients, and one or more fillers, and a coatingcomprising either a sugar or one or more acrylic polymers and/orcopolymers. The oral dosage formulation of the present inventionincludes in one aspect, a tablet having a core and a coating. The tabletmay be made in accordance with a variety of techniques known to thoseskilled in the pharmaceutical arts. For example, the core may contain asimple admixture of particulate, or beaded ingredients, as is known, orbeads may be provided that have specific configurations, such as aninner center of excipient, surrounded by a conjugated estrogen. Otherpossible core configurations will be readily recognized by those skilledin the art.

The conjugated estrogens of the present invention are those generallyknown and described in the art as conjugated estrogens. See UnitedStates Pharmacopia (USP 23). While conjugated estrogens are typically amixture of estrogenic components, such as estrone and equilin, thepresent invention may be formulated to either utilize such a mixture, orto include only selected or individual estrogenic components. Theseconjugated estrogens may be of synthetic or natural origin. Naturallyoccurring conjugated estrogens are obtained from pregnant mare urine andthen are processed and may be stabilized. Examples of such processes areset forth in U.S. Pat. Nos. 2,565,115 and 2,720,483, each of which areincorporated herein by reference. Many conjugated estrogen products arenow commercially available.

Conjugated estrogens are also made synthetically. Examples ofsynthetically produced estrogens include estropipate and ethinylestradiol. “Conjugated estrogens” as used herein includes both naturaland synthetic conjugated estrogens, such as the Pharmacopia inclusivecompounds alluded to above, as well as other estrogens so considered bythose skilled in the art. Further, “conjugated estrogens” refers toesters of such compounds, such as the sulfate esters, salts of suchcompounds, such as sodium salts, and esters of the salts of suchcompounds, such as sodium salts of a sulfate ester, as well as otherderivatives known in the art. Some specific examples include: 17-alphaand beta-dihydroequilin, equilenin, 17-alpha and beta-dihydroequilenin,estrone, 17-beta-estradiol, and their sodium sulfate esters.

The specific conjugated estrogen dose included in the tablet of thepresent invention may be any dosage required to achieve a specifictherapeutic effect, and may vary depending on the specific treatmentindicated, and on the specific conjugated estrogen included in thetablet. However, in general, dosages of conjugated estrogens included inthe tablet, can range from about 0.2 mg/tablet to about 3.0 mg/tablet.

In addition, the present dosage forms can include other hormones such asprogestins and androgens. Such hormones may be incorporated either intothe core or coating of the present tablet, as discussed further below.Specific progestins that may be used include without limitation:progesterone, medroxyprogesterone, and a variety of synthetic progestinsand their salts, esters, and derivatives that are generally known andused in the oral contraceptive area. Specific androgens that may beused, include without limitation, testosterone, methyltestosterone, andother known derivatives and their esters and salts, including deconoate,cypionate, propionate, etc. Any of these hormones can also bemicronized.

The inorganic excipients include calcium phosphate tribasic, and calciumcarbonate. The calcium phosphate tribasic is present at less than about20% of the weight of the composition. In some aspects, the calciumphosphate tribasic is present at less than about 15% by weight; in someaspects, less than about 10% by weight; in some aspects, it is less than8% by weight; and in some aspects, it is less than 5% by weight of thecomposition. In one aspect, it has been discovered that when the calciumphosphate tribasic is present at these proportions, the physicalstability of the composition is greatly increased during storage, forexample by reduced cracking, as compared to those compositions of U.S.Pat. No. 5,908,638.

The invention also comprises one or more organic excipients in thetablet core, such as a cellulose ingredient. In one aspect, thecellulose may be hydroxypropylmethylcellulose. Other excipients that canbe used in the core of the composition include without limitation:hydroxypropyl cellulose, carboxymethylcellulose, ethyl cellulose, methylcellulose, their derivatives and salts. Additionally, other organicexcipients, polyethylene glycol, talc, lactose, starch, sorbitol,mannitol, polyvinylpyrrolidone can also be used.

In one particular aspect, lactose may be included in the core, whereinthe lactose is present at less than about 50% by weight of theformulation. In one aspect, the lactose may be present in an amount offrom about 1% to about 50% by weight. In some aspects, the lactose ispresent from about 10% to about 50% by weight; in some aspects, fromabout 10% to about 40%; in some other aspects, from about 10% to about30% by weight; in yet other aspects, from about 5% to about 30% byweight; in yet some other aspects, from about 5% to about 50% by weight.In one aspect, lactose is present from about 20% to about 30% by weight.

Notwithstanding the above-recited core ingredients and amountstherefore, in one aspect, the tablet of the present invention mayinclude gel forming excipients, such as various celluloses and gelatins,in an amount of less than about 25% w/w of the composition. In use, suchexcipients form a gel in an aqueous solution, and therefore, when thetablet coating is penetrated by digestive fluids, the core swells andruptures the coating to facilitate release of the conjugated estrogen.In another aspect of the invention, the amount of gel forming excipientsmay be less than about 20% w/w of the composition. In yet anotheraspect, the amount may be less than about 15% w/w of the composition.

The coating for the tablet of the present invention may be made from awide variety of materials including sugars and acrylic polymers andcopolymers. Of particular note is that in one aspect, no hormones arecontained in the coating. In other aspects, the coating may containhormones in addition to a variety of other ingredients known to thoseskilled in the art, such as plasticizers, colorants, and solvents orother vehicles. Notably, such ingredients create a barrier that isinitially soluble in gastrointestinal fluid, in order to achieve aninitial drug release. By contrast, many sustained release formulations,such as the formulation disclosed in U.S. Pat. No. 5,908,638 requirethat the tablet coating provide a coating that is impervious to stomachfluid for at least the first few hours. As such, in one aspect, thetablet of the present invention may include a coating that providesinitial drug release while in the stomach of a subject. In anotheraspect, initial drug release may occur in less than about 2 hours afteradministration. In yet another aspect, initial drug release may occur inless than about 1 hour after administration.

A wide variety of sugars may be used for the coating of the presentinvention as known to those skilled in the art. Examples of suitablesugars include without limitation, sucrose derived from a variety ofsources, such as beet or cane sources, starch, saccharid orpolysaccharide converted sources, and which is considered suitable foruse in pharmaceutical applications.

A number of acrylic polymers or copolymers known to those skilled in theart may also be used to form the coating of the tablet of the presentinvention. Examples of specific polymers include without limitation,polymers of acrylic esters, such as methacrylate, and methylmethacrylate copolymers. Various acceptable polymers may be obtain froma variety of commercial sources, such as EUDRAGIT® polymers availablefrom Rohm and Haas Corporation. In one aspect, the coating may include amixture or blend of acrylic polymers or copolymers. In another aspect,the mixture may be present at a ratio of from about 1:10 to about 10:1.In a further aspect, the ratio may be from about 1:5 to 5:1. In yetanother aspect, the ratio may be from about 1:2 to about 2:1.

The present invention is distinct from the previously known and/ordisclosed formulations in at least the following ways:

a) in the presence of lactose or similar sugar excipient in an amount ofabout or less than 50% by weight, or from about 5%-50% by weight, orfrom about 10%-40% by weight, or from about 10%-30% by weight; or fromabout 20%-30% by weight;

b) in the presence of calcium phosphate tribasic at less than 20% byweight; or from about 5%-20% by weight; or from about 5%-15% by weight;or from about 1%-15% by weight; or from about 1%-10% by weight; or fromabout 5%-10% by weight;

c) in the absence of a substantial amount of a hormone in the outercoating layer in some embodiments;

d) in the absence of a substantial amount of a microcrystallinecellulose in the outer coating layer to aid in controlling the releaseof the drug from the core;

e) in the absence of a substantial amount of a moisture barrierimparting polymer (i.e. ethyl cellulose) as an outer coat that preventsdissolution in the gastrointestinal fluid of the stomach, and thereforeprevents of minimizes drug release in the stomach; and

f) in the presence.of gel forming excipients in an amount of less thanabout 25% w/w of the composition; 20% w/w of the composition, 15% w/w orfrom about 1% w/w to about 25% w/w of the composition.

It has been discovered that when the composition for conjugatedestrogens comprises the above distinct characteristics, the compositiondoes not crack over long storage times, provides a drug release that isvery comparable to the commercially successful product known anPremarin®, and yet is simple to prepare. The prior known or disclosedcompositions, although used commercially, have a lacked one or more ofthe above characteristics and therefore have the need to be improved foroptimal stability and patient acceptance.

More specifically, the U.S. Pat. No. 5,547,948 discloses a corecomprising conjugated estrogens and excipients and a sugar coat thatalso comprises a hormone and microcrystalline cellulose to control therelease of the hormone from the coating. The invention in the '948patent is directed at delivering the hormone in the sugar coating, anddoes not teach or suggest compositions that deliver conjugated estrogensfrom the core wherein such compositions comprise inorganic excipientssuch as calcium phosphate tribasic and yet that do not crack. Incontrast, the present invention does not comprise a sugar coat thatcontrols the release of the hormone.

The U.S. Pat. No. 5,395,627 teaches hormonal dosage forms wherein thecore is made up of desogestrel, ethinylestradiol, and lactose andpolyvinylpyrrolidone, among others, and a film coat comprising HPMC andPEG. The specification teaches diluents such as lactose from about 70%to about 95% by weight of the composition and does not teach theinclusion of about conjugated estrogens. In contrast, the excipients ofthe present invention comprise lactose at about or less than about 50%by weight and contain an inorganic excipient such as calcium phosphatetribasic and comprise conjugated estrogens.

The U.S. Pat. No. 5,720,977 teaches formulations comprising estropipate,calcium glycerophosphate, citric acid, and sodium bicarbonate to provideeffervescence. Estropipate, which can also be used in the presentinvention, is admittedly distinct from naturally occurring conjugatedestrogens in that the latter are highly moisture sensitive, whereasestropipate is known to be “stable.” See, column 3, lines 17-25.

The U.S. Pat. No. 5,908,638 teaches that in order to accomplish stableconjugated estrogen formulations: a) the moisture content must be lessthan 2.5% free water; b) inorganic excipients should not be present; c)shellac coating should be avoided; c) the core tablets must be coatedusing a moisture barrier material. See, columns 7, 8, 10, and 14. Thispatent teaches that water bound to organic excipients do not cause anydeleterious effects to the conjugated estrogens. See column 8, lines39-41.

In contrast to these teachings, the present invention comprises aninorganic excipient, in some embodiments a shellac coating, and does notcontain a moisture barrier coating, but only a sugar coating or anacrylic coating. Further, it is believed, without wishing to be bound byany theory, that the particular combination of one or more of the aboveunique characteristics result in conjugated estrogen formulations thatdeliver the drug at rates comparable to the commercially successfulPremarin® formulation, without cracking on extended storage, such as forone month, or two months or longer, under accelerated stabilitytemperature and humidity conditions. Or, of a more practical nature, asindicated by passing accelerated stability tests, the compositions ofthe present invention are stable and do not crack over an extendedperiod of time under at ambient conditions of temperature and humidityas found in various environments.

One contributing factor to the success of the present inventions may be,again without wishing to be bound by any theory, the presence of lactosein lower amounts (i.e., at about or less than 50% by weight and otheramounts disclosed herein) than in the previously disclosed formulationsof conjugated estrogens. Another contributing factor may be, againwithout wishing to be bound by any theory, the presence of low amounts(less than or about 20% by weight or other amounts as disclosed herein)of calcium compound such as calcium phosphate tribasic. It is alsopossible that one or more of these factors taken either alone, or incombination contribute to the desired physical characteristics describedabove.

A variety of conventional methods known to those skilled in the art maybe used to produce the tablets of the present invention. Examples ofsuch methods, such as wet granulation, fluid-bed granulation, drygranulation, and direct compression may be found in Remmington'sPharmaceutical Sciences pp. 1615-1649 (19^(th) ed. 1995).

EXAMPLE 1

The active bulk ingredients were weighed and comminuted withhydroxypropylmethyl cellulose (Methocel K-3) under nitrogen atmosphere.The mixture was passed through a #20 mesh screen. The resulting mixturewas blended with dehydrated alcohol under nitrogen atmosphere and driedwith a loss on drying no greater than 2.5%. The dried mixture was thenagain passed through a Mesh #20 screen. The mixture was then blendedwith calcium phosphate tribasic, lactose (Fast-flo316) andmicrocrystalline cellulose (Avicel PH 113), again under nitrogenatmosphere. This mixture was further treated with stearic acid andmagnesium stearate as lubricants. The resulting blend was dried againwith a loss on drying no more than 2.5%. The dried mixture was thencompressed into tablets on a rotary tablet press.

EXAMPLE 2

Tablets prepared as in Example 1, and having a core composition as shownin Table 1, were placed in a 24″ Accelacota Side Vented coating pan andcoated with shellac. This was followed by another coating of sugar. Theresulting sugar-coated tablets were cured for 24 hours in a nary oven at50° C. The composition of the sugar-coated tablets is given in thefollowing Table 1.

TABLE 1 Composition of sugar-coated 0.625 mg conjugated estrogenstablets Ingredient Mg/tablet CORE Conjugated estrogens 0.625 MethocelK-3 Prem. LV 40.0 Lactose (Fast-flo316) 55.5 Calcium Phosphate Tribasic,USP 7.0 Avicel PH 113 26.0 Stearic Acid 0.65 Magnesium Stearate NF 0.65#4 Refined Pharmaceutical Glaze, NF in 45/200 7.2 Alcohol (solid) Talc,USP (Alphafil 500) 7.2 COATING Sucrose, NF 111.3 Calcium Sulfate, NF6.23 Talc, USP 2.25 PEG 8000, USP 0.09 Carnuba Wax, NF 0.15 Total 264.8mg/tablet

EXAMPLE 3

Tablets as prepared in Example 1, and having the core composition as inTable 2, were placed in a 24″ Accelacota Side Vented coating pan andcoated with methacrylic acid copolymers. Such copolymers arecommercially known as Eudragit RL30D and Eudragit RS30D. The resultingacrylic-coated tablets were cured for 24 hours in a nary oven at 50° C.The composition for the acrylic coated tablets is given in the followingTable 2.

TABLE 2 Composition of acrylic-coated 0.625 mg conjugated estrogenstablets Ingredient Mg/tablet CORE Conjugated estrogens 0.625 MethocelK-3 Prem. LV 40.0 Lactose (Fast-flo316) 55.5 Calcium Phosphate Tribasic,USP 6.5 Avicel PH 113 26.0 Stearic Acid 0.65 Magnesium Stearate NF 0.65Talc, USP (Alphafil 500) 5.35 COATING Eudragit RS-30D 4.88 (solid)Eudragit RL-30D 2.44 (solid) Triethyl citrate 0.33 Antifoam 0.70Opadryl, Clear (YS-1-10925-A) 1.3 Total 144.9 mg/tablet

EXAMPLE 4

Stability and drug release rates were studied for sugar-coated tabletsas prepared in Example 1 and Table 1. Stability was monitored underdifferent storage conditions. These conditions included: 50° C., 75%relative humidity, after two weeks; 40° C., 75 % relative humidity,after one month; 40° C., 75% relative humidity, after two months. Thesamples were monitored for various active compounds and degradationproducts as specified in the USP. The data are shown in Table 3. Thesedata indicate that the sugar-coated tablets of the present inventionwere stable under all these accelerated conditions. This is establishedby the fact that the various active compounds and the degradationproducts were within the specified limits for USP.

TABLE 3 0.625 mg Coated (Sugar) Tablets Conjugated Estrogens - StabilityStudies Product: 0.625 mg Coated Tablets Lot # EXPWS 1246 Coating R & Ds/n 001659 001752 002163 002300 Storage condition Initial 50c, 75% RH/2wks 40c, 75% RH/1 mth 40c, 75% RH/2 mth USP limits % Found % Found %Initial % Found % Initial % Found % Initial Estrone 52.5-61.5% 49.1 50.8103.5 50.2 102.2 50.2 102.2 Equilin 22.5-30.5% 22.7 23.3 102.6 23.0101.3 23 101.3 Estrone + Equilin 79.5-88.0% 71.8 74.0 103.1 73.2 101.973.2 101.9 17a-dihydroequilin 13.5-19.5% 14.0 14.5 103.6 14.3 102.1 14.5103.6 17a-estradiol 2.5-9.5% 3.8 3.8 100.0 3.9 102.6 3.9 102.617b-estradiol <2.25% 0.60 0.59 98.3 0.56 93.3 0.62 103.317b-dihydroequilin 0.5-4.0% 1.3 1.3 100.0 1.3 100.0 1.4 107.717a-dihydroequilenin <3.25% 2.05 2.19 106.8 2.16 105.4 2.2 107.317b-dihydroequilenin <2.75% 0.56 0.63 112.5 0.58 103.6 0.44 78.6d8,9-dehydroesterone <6.25% 4.72 4.91 104.0 4.68 99.2 4.53 96.0Equilenin <5.5% 2.6 2.6 107.7 2.8 107.7 2.8 107.7 Equilin/Estrone0.35-0.65 0.46 0.46 100.0 0.46 100.0 0.46 99.7 LOD % 1.15 1.79 1.55 1.33

EXAMPLE 5

Stability and drug release rates were studied for acrylic-coated tabletsmade in accordance with Example 1 and Table 2. Stability was monitoredunder different storage conditions. These conditions included: 50° C.,75% relative humidity, after two weeks; 40° C., 75 % relative humidity,after one month; 40° C., 75% relative humidity, after two months. Thesamples were monitored for various active compounds and degradationproducts as specified in the USP. The data are shown in Table 4. Thesedata indicate that the acrylic-coated tablets of the present inventionwere stable under all these accelerated conditions. This is establishedby the fact that the various active compounds and the degradationproducts were within the specified limits for USP.

TABLE 4 0.625 mg Coated (acrylic) Tablets Conjugated Estrogens -Stability Studies Product: 0.625 mg Coated Tablets Lot # EXPWS 1251Coating 10% Eudragt/ RS:RL(2:1) R & D s/n 001560 001656 001767 002084002298 Storage condition Initial 50c, 75% RH/2 wks 40c, 75% RH/1 m 40c,75% RH/2 m 40c, 75% RH/3 m % % % % USP limits % Found Found % InitialFound % Initial Found % Initial Found % Initial Change Estrone52.5-61.5% 55.9 55.2 96.7 56.6 101.3 55.9 100.0 56.4 100.9 −0.5 Equilin22.5-30.5% 27.3 26.5 97.1 27.1 99.3 26.5 97.1 26.4 96.7 0.9 Estrone +Equilin 79.5-88.0% 83.2 81.7 96.2 83.6 100.5 82.4 99.0 82.9 99.6 0.317a-dihydroequilin 13.5-19.5% 17.9 17.4 97.2 17.9 100.0 17.6 96.3 18.1101.1 −0.2 17a-estradiol 2.5-9.5% 4.6 4.5 97.8 4.7 102.2 4.7 102.2 4.8104.3 −0.2 17b-estradiol <2.25% 1.26 1.11 88.1 0.90 71.4 0.96 76.2 0.8869.8 0.38 17b-dihydroequilin 0.5-4.0% 2.3 2.2 95.7 2.5 106.7 2.4 104.32.4 104.3 −0.1 17a-dihydroequilenin <3.25% 1.65 1.79 106.5 2.03 123.02.34 141.8 2.82 170.9 −1.17 17b-dihydroequilenin <2.75% 0.77 0.67 87.00.97 126.0 0.86 111.7 0.68 88.3 0.09 d8,9-dehydroesterone <6.25% 4.154.07 96.1 4.13 99.5 4.02 96.9 3.91 94.2 0.24 Equilenin <5.5% 2.2 2.5113.6 2.3 104.5 2.6 118.2 3.0 136.4 −0.8 Equilin/Estrone 0.35-0.65 0.490.48 98.0 0.48 97.6 0.47 96.7 0.47 95.6 0.02 LOD % 2.52 2.35 2.94 3.043.18

EXAMPLE 6

The drug release profile was obtained for the sugar-coated conjugatedestrogen tablets of the present invention. Standard USP methodology wasfollowed, which included using distilled water (900 ml), paddles at 50rpm. The data were displayed graphically as shown in FIG. 1. A positivecontrol of Premarin® was used to validate further the data.

These data indicate that at least some sugar-coated tablets of thepresent invention release under some conditions the conjugated estrogensat approximately the same rate as the Premarin product®.

EXAMPLE 7

The drug release profile was obtained for the acrylic-coated conjugatedestrogen tablets of the present invention. Standard USP methodology wasfollowed, which included using distilled water (900 ml), paddles at 50rpm. The data were displayed graphically as shown in FIG. 2. A positivecontrol of Premarin® was used to validate further the data.

These data indicate that acrylic-coated tablets of the present inventionrelease the conjugated estrogens at approximately the same rate as thePremarin product®. This release rate is noted to be closer for allconditions tested.

Of course, it is to be understood that the above-described arrangementsare only illustrative of the application of the principles of thepresent invention. Numerous modifications and alternative arrangementsmay be devised by those skilled in the art without departing from thespirit and scope of the present invention and the appended claims areintended to cover such modifications and arrangements. Thus, while thepresent invention has been described above with particularity and detailin connection with what is presently deemed to be the most practical andpreferred embodiments of the invention, it will be apparent to those ofordinary skill in the art that numerous modifications, including, butnot limited to, variations in size, materials, shape, form, function andmanner of operation, assembly and use may be made without departing fromthe principles and concepts set forth herein.

What is claimed is:
 1. A pharmaceutical composition in a solid oraldosage form comprising: a core containing a therapeutically effectiveamount of at least one conjugated estrogen, or a component thereof, andat least one organic excipient, wherein the at least one organicexcipient comprises less than about 25% w/w of a cellulose ingredient,and less than about 50% w/w of a sugar ingredient, and at least oneinorganic excipient, wherein the at least one inorganic excipientcomprises a calcium phosphate tribasic ingredient; and apharmaceutically acceptable coating that is free of hormones, whereinthe composition does not crack when stored at 40° C. and 75% relativehumidity for about two months.
 2. The pharmaceutical composition ofclaim 1, wherein the therapeutically effective amount of conjugatedestrogen is from about 0.1 mg to about 3 mg.
 3. The pharmaceuticalcomposition of claim 2, wherein the amount is about 0.625 mg.
 4. Thepharmaceutical composition of claim 1, wherein the coating is a sugarcoating.
 5. The pharmaceutical composition of claim 1, wherein thecoating is an acrylic coating.
 6. A pharmaceutical composition in asolid oral dosage form comprising: a core containing a therapeuticallyeffective amount of a conjugated estrogen, or a hormonal componentthereof, and at least one organic excipient, wherein the at least oneorganic excipient comprises less than about 25% w/w of a celluloseingredient, and less than about 50% w/w of a sugar ingredient, and atleast one inorganic excipient, wherein the at least one organicexcipient comprises a calcium phosphate tribasic ingredient; and apharmaceutically acceptable sugar coating, wherein the composition doesnot crack when stored at 40° C. and 75% relative humidity for about twomonths.
 7. The composition of claim 6, wherein the therapeuticallyeffective amount of conjugated estrogen is from about 0.1 mg to about 3mg.
 8. The pharmaceutical composition of claim 7, wherein the amount isabout 0.625 mg.
 9. A pharmaceutical composition in a solid oral dosageform comprising: a core containing a therapeutically effective amount ofa conjugated estrogen, or a hormonal component thereof, and at least oneorganic excipient, wherein the at least one organic excipient comprisesless than about 25% w/w of a cellulose ingredient, and less than about50% w/w of a sugar ingredient and at least one inorganic excipient,wherein the at least one organic excipient comprises a calcium phosphatetribasic ingredient; and a pharmaceutically acceptable acrylic coating,wherein the composition does not crack when stored at 40° C. and 75%relative humidity for about two months.
 10. The pharmaceuticalcomposition of claim 9, wherein the therapeutically effective amount ofconjugated estrogen is from about 0.1 mg to about 3 mg.
 11. Thepharmaceutical composition of claim 10, wherein the amount is about0.625 mg.